Activation of the STING-Dependent Type I Interferon Response Reduces Microglial Reactivity and Neuroinflammation
Open accessAbstract
Brain aging and neurodegeneration are associated with prominent microglial reactivity and activation of innate immune response pathways, commonly referred to as neuroinflammation. One such pathway, the type I interferon response, recognizes viral or mitochondrial DNA in the cytoplasm via activation of the recently discovered cyclic dinucleotide synthetase cGAS and the cyclic dinucleotide receptor STING. Here we show that the FDA-approved antiviral drug ganciclovir (GCV) induces a type I interferon response independent of its canonical thymidine kinase target. Inhibition of components of the STING pathway, including STING, IRF3, Tbk1, extracellular IFNβ, and the Jak-Stat pathway resulted in reduced activity of GCV and its derivatives. Importantly, functional STING was necessary for GCV to inhibit inflammation in cultured myeloid cells and in a mouse model of multiple sclerosis. Collectively, our findings uncover an unexpected new activity of GCV and identify the STING pathway as a regulator of microglial reactivity and neuroinflammation.
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The protein machinery required to detect cytosolic DNA such as STING is reported to be low in neurons compared to glial cells.
“Indeed, the protein machinery required to detect cytosolic DNA such as STING is reported to be low in neurons compared to glial cells (Mathur et al, 2017; Song et al, 2019).”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Mathur et al, 2017
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References 57 · Cited by 175
- Authors
- Mathur, V., Burai, R., Vest, R. T., Bonanno, L. N., Lehallier, B., Zardeneta, M. E., Mistry, K. N., Do, D., Marsh, S. E., Abud, E. M., Blurton-Jones, M., Li, L., Lashuel, H. A., & Wyss-Coray, T.
- Affiliations
- VA Palo Alto Health Care System (US)
- École Polytechnique Fédérale de Lausanne (CH)
- Stanford University (US)
- Stanford Medicine (US)
- University of California, Irvine (US)
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2017-12
- Volume
- 96
- Issue
- 6
- Pages
- 1290-1302.e6
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC5806703
- OpenAlex
- W2770682151
- Cited by
- 175
- References
- 57
- Citations by year
- 2026: 22 · 2025: 22 · 2024: 22 · 2023: 20 · 2022: 24 · 2021: 30 · 2020: 14 · 2019: 14 · 2018: 6 · 2017: 1
- FWCI
- 4.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Funders
- Bluefield Project to Cure Frontotemporal Dementia
- Department of Veterans Affairs (IO1 RX001218)
- National Institute on Aging (AG045034)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Keywords
- STING, type I interferon response, microglial activation, neuroinflammation, ganciclovir, cGAS, IRF3, TBK1, JAK/STAT signaling, multiple sclerosis, brain aging, neurodegeneration, antiviral agents, innate immunity
- MeSH terms
- STING Protein, Animals, Animals, Newborn, Antiviral Agents, Cells, Cultured, Disease Models, Animal, Encephalomyelitis, Autoimmune, Experimental, Female, Freund's Adjuvant, Gene Expression Regulation, Humans, Interferon Type I, Male, Membrane Proteins, Mice, Inbred C57BL, Mice, Transgenic, Monocytes, Peptide Fragments, Signal Transduction, Ganciclovir, Microglia, Pertussis Toxin, Mice, Myelin-Oligodendrocyte Glycoprotein
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